Histoplasmosis Guidelines 2007

IDSA GUIDELINES
Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America
L. Joseph Wheat,1 Alison G. Freifeld,3 Martin B. Kleiman,2 John W. Baddley,4,5 David S. McKinsey,6 James E. Loyd,7 and Carol A. Kauffman8
1
MiraVista Diagnostics/MiraBella Technologies and 2Indiana University School of Medicine, Indianapolis, Indiana; 3University of Nebraska Medical Center, Omaha; 4University of Alabama at Birmingham and 5Birmingham Veterans Affairs Medical Center, Alabama; 6ID Associates of Kansas City, Missouri; 7Vanderbilt University Medical Center, Nashville, Tennessee; and 8Veterans Affairs Medical Center, University of Michigan Medical School, Ann Arbor
Evidence-based guidelines for the management of patients with histoplasmosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 30:68895). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. Since 2000, several new antifungal agents have become available, and clinical trials and case series have increased our understanding of the management of histoplasmosis. Advances in immunosuppressive treatment for inammatory disorders have created new questions about the approach to prevention and treatment of histoplasmosis. New information, based on publications from the period 19992006, are incorporated into this guideline document. In addition, the panel added recommendations for management of histoplasmosis in children for those aspects that differ from aspects in adults. EXECUTIVE SUMMARY
Background
Histoplasma capsulatum variety capsulatum infection is endemic in certain areas of North, Central, and South America, Africa, and Asia, but cases have also been reported from Europe. In the United States, most cases
Received 18 June 2007; accepted 19 June 2007; electronically published 27 August 2007. These guidelines were developed and issued on behalf of the Infectious Diseases Society of America. It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. The Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patients individual circumstances. Reprints or correspondence: Dr. L. Joseph Wheat, MiraVista Diagnositics/ MiraBella Technologies, 4444 Decatur Blvd., Ste. 300, Indianapolis, IN 46241 (jwheat@miravistalabs.com). Clinical Infectious Diseases 2007; 45:80725 2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4507-0001$15.00 DOI: 10.1086/521259
have occurred within the Ohio and Mississippi River valleys. Precise reasons for this distribution pattern of endemicity are unknown but are thought to include moderate climate, humidity, and soil characteristics. Bird and bat excrement enhances the growth of the organism in soil by accelerating sporulation. These unique growth requirements explain, in part, the localization of histoplasmosis into so-called microfoci. Activities that disturb such sites are associated with exposure to H. capsulatum. Air currents carry the conidia for miles, exposing individuals who were unaware of contact with the contaminated site. Furthermore, environmental sites that are not visibly contaminated with droppings may harbor the organism, making it difcult to suspect histoplasmosis in most cases. Certain forms of histoplasmosis cause life-threatening illnesses and result in considerable morbidity, whereas other manifestations cause no symptoms or minor self-limited illnesses. The objective of this guideline is to update recommendations for treating patients with histoplasmosis.
IDSA Guidelines for Management of Histoplasmosis CID 2007:45 (1 October) 807
Treatment of Acute and Chronic Pulmonary Histoplasmosis
Moderately Severe to Severe Acute Pulmonary Histoplasmosis 1. Lipid formulation of amphotericin B (3.05.0 mg/kg daily intravenously for 12 weeks) followed by itraconazole (200 mg 3 times daily for 3 days and then 200 mg twice daily, for a total of 12 weeks) is recommended (A-III). 2. The deoxycholate formulation of amphotericin B (0.7 1.0 mg/kg daily intravenously) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (A-III). 3. Methylprednisolone (0.51.0 mg/kg daily intravenously) during the rst 12 weeks of antifungal therapy is recommended for patients who develop respiratory complications, including hypoxemia or signicant respiratory distress (B-III). Mild-to-Moderate Acute Pulmonary Histoplasmosis 4. Treatment is usually unnecessary (A-III). Itraconazole (200 mg 3 times daily for 3 days and then 200 mg once or twice daily for 612 weeks) is recommended for patients who continue to have symptoms for 11 month (B-III). Chronic Cavitary Pulmonary Histoplasmosis 5. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for at least 1 year) is recommended, but some prefer 1824 months in view of the risk for relapse (A-II). 6. Blood levels of itraconazole should be obtained after the patient has been receiving this agent for at least 2 weeks to ensure adequate drug exposure (A-III).
Complications
12. Prednisone (0.51.0 mg/kg daily [maximum, 80 mg daily] in tapering doses over 12 weeks) is recommended in severe cases (B-III). 13. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for 612 weeks) is recommended only if corticosteroids are administered (B-III). Mediastinal Lymphadenitis 14. Treatment is usually unnecessary (A-III). 15. Itraconazole (200 mg 3 times daily for 3 days and then 200 mg once or twice daily for 612 weeks) is recommended in patients who have symptoms that warrant treatment with corticosteroids and in those who continue to have symptoms for 11 month (B-III). 16. Prednisone (0.51.0 mg/kg daily [maximum, 80 mg daily] in tapering doses over 12 weeks) is recommended in severe cases with obstruction or compression of contiguous structures (B-III). Mediastinal Granuloma 17. Treatment is usually unnecessary (A-III) 18. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for 612 weeks) is recommended for symptomatic cases (B-III). Mediastinal Fibrosis 19. Antifungal treatment is not recommended (A-III). 20. The placement of intravascular stents is recommended for selected patients with pulmonary vessel obstruction (B-III). 21. Itraconazole (200 mg once or twice daily for 12 weeks) is recommended if clinical ndings cannot differentiate mediastinal brosis from mediastinal granuloma (C-III). Broncholithiasis 22. Antifungal treatment is not recommended (A-III). 23. Bronchoscopic or surgical removal of the broncholith is recommended (A-III). Pulmonary Nodules (Histoplasmomas) 24. Antifungal treatment is not recommended (A-III).
Progressive Disseminated Histoplasmosis
Pericarditis 7. Nonsteroidal anti-inammatory therapy is recommended in mild cases (B-III). 8. Prednisone (0.51.0 mg/kg daily [maximum, 80 mg daily] in tapering doses over 12 weeks) is recommended for patients with evidence of hemodynamic compromise or unremitting symptoms after several days of therapy with nonsteroidal anti-inammatory therapy (B-III). 9. Pericardial uid removal is indicated for patients with hemodynamic compromise (A-III). 10. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for 612 weeks) is recommended if corticosteroids are administered (B-III). Rheumatologic Syndromes 11. Nonsteroidal anti-inammatory therapy is recommended in mild cases (B-III).
25. For moderately severe to severe disease, liposomal amphotericin B (3.0 mg/kg daily) is recommended for 12 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days and then 200 mg twice daily for a total of at least 12 months) (A-I). 26. Substitution of another lipid formulation at a dosage of 5.0 mg/kg daily may be preferred in some patients because of cost or tolerability (A-III). 27. The deoxycholate formulation of amphotericin B
808 CID 2007:45 (1 October) Wheat et al.
(0.71.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (A-III). 28. For mild-to-moderate disease, itraconazole (200 mg 3 times daily for 3 days and then twice daily for at least 12 months) is recommended (A-II). 29. Lifelong suppressive therapy with itraconazole (200 mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed (A-II) and in patients who relapse despite receipt of appropriate therapy (C-III). 30. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (B-III). 31. Antigen levels should be measured during therapy and for 12 months after therapy is ended to monitor for relapse (B-III). Persistent low-level antigenuria may not be a reason to prolong treatment in patients who have completed appropriate therapy and have no evidence of active infection.
Prophylaxis for Immunosuppressed Patients
mg/kg daily) is usually well tolerated, and the lipid preparations are not preferred (A-III). 40. Itraconazole dosage in children is 5.010.0 mg/kg daily in 2 divided doses (not to exceed 400 mg daily), generally using the solution formulation (A-III). Progressive Disseminated Histoplasmosis 41. Amphotericin B deoxycholate (1.0 mg/kg daily for 4 6 weeks) is recommended (A-III). 42. Amphotericin B deoxycholate (1.0 mg/kg daily for 2 4 weeks) followed by itraconazole (5.010.0 mg/kg daily in 2 divided doses) to complete 3 months of therapy is an alternative (A-III). 43. Longer therapy may be needed for patients with severe disease, immunosuppression, or primary immunodeciency syndromes (A-III). 44. Lifelong suppressive therapy with itraconazole (5.0 mg/kg daily, up to 200 mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed (A-II) and in patients who experience relapse despite receipt of appropriate therapy (C-III). 45. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (B-III). 46. Antigen levels should be monitored during therapy and for 12 months after therapy is ended to monitor for relapse (B-III). Persistent low-level antigenuria may not be a reason to prolong treatment in patients who have completed appropriate therapy and have no evidence of active infection. INTRODUCTION In 2000, the Infectious Diseases Society of America (IDSA) published a clinical practice guideline on the management of patients with histoplasmosis [1]. The IDSA updates its guidelines when new data or publications might change a prior recommendation or when the panel feels clarication or additional guidance is warranted. For the 2007 update, the indications for treatment and agents of choice from the 2000 guideline were reviewed [1]. The previous document is a source for a more detailed review of earlier studies. Areas related to several newer antifungal agents and immunosuppressive regimens for chronic inammatory disorders were not previously covered, because there was limited information at the time. Therefore, the panel decided to include them in this update. The panel addressed the following clinical questions in the 2007 update. 1. What is the treatment for acute and chronic pulmonary histoplasmosis? 2. What is the treatment for complications of pulmonary
32. Prophylaxis with itraconazole (200 mg daily) is recommended in patients with HIV infection with CD4 cell counts !150 cells/mm3 in specic areas of endemicity where the incidence of histoplasmosis is 110 cases per 100 patient-years (A-I). 33. Prophylaxis with itraconazole (200 mg daily) may be appropriate in specic circumstances in other immunosuppressed patients (C-III).
CNS Histoplasmosis
34. Liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 46 weeks) followed by itraconazole (200 mg 2 or 3 times daily) for at least 1 year and until resolution of CSF abnormalities, including Histoplasma antigen levels, is recommended (B-III). 35. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (B-III).
Histoplasmosis in Pregnancy
36. Lipid formulation amphotericin B (3.05.0 mg/kg daily for 46 weeks) is recommended (A-III). 37. The deoxycholate formulation of amphotericin B (0.71.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (A-III). 38. If the newborn shows evidence for infection, treatment is recommended with amphotericin B deoxycholate (1.0 mg/kg daily for 4 weeks) (A-III).
Histoplasmosis in Children
Acute Pulmonary Histoplasmosis 39. Treatment indications and regimens are similar to those for adults, except that amphotericin B deoxycholate (1.0
Table 1. Infectious Diseases Society of AmericaUnited States Public Health Service grading system for ranking recommendations in clinical guidelines.
Category, grade Strength of recommendation A B C Quality of evidence I II Good evidence to support a recommendation for use Moderate evidence to support a recommendation for use Poor evidence to support a recommendation Evidence from 1 properly randomized, controlled trial Evidence from 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from 11 center); from multiple time-series; or from dramatic results from uncontrolled experiments Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees Denition
III
NOTE. Adapted from Canadian Task Force on the Periodic Health Examination [3].
histoplasmosis (e.g., pericarditis, arthritis/erythema nodosum, mediastinal lymphadenitis, mediastinal granuloma, mediastinal brosis, broncholithiasis, and pulmonary nodule)? 3. What is the treatment for progressive disseminated histoplasmosis? 4. Is prophylaxis recommended for immunocompromised patients? 5. What is the treatment for CNS histoplasmosis? 6. What is the treatment for histoplasmosis in pregnancy? 7. What treatment is recommended for histoplasmosis in children?
toplasma and focused on human studies but included a few studies from experimental models of histoplasmosis.
Process Overview
In evaluating the evidence regarding the management of histoplasmosis, the panel followed a process used in the development of other IDSA guidelines. The process included a systematic weighting of the quality of the evidence and the grade of recommendation (table 1) [3].
Consensus Development Based on Evidence
PRACTICE GUIDELINES Practice guidelines are systematically developed statements to assist practitioners and patients in making decisions about appropriate health care for specic clinical circumstances [2]. Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, clinical exibility, clarity, multidisciplinary process, review of evidence, and documentation [2]. UPDATE METHODOLOGY
Panel Composition
The panel met on 6 occasions via teleconference to complete the work of the guideline. The purpose of the teleconferences was to discuss the questions to be addressed, make writing assignments, and discuss recommendations. All members of the panel participated in the preparation and review of the draft guideline. Feedback from external peer reviews was obtained. The guideline was reviewed and approved by the IDSA Standards and Practice Guidelines Committee (SPGC) and the Board of Directors prior to dissemination.
Guidelines and Conicts of Interest
The IDSA Standards and Practice Guidelines Committee (SPGC) convened experts in the management of patients with histoplasmosis. The panel members are listed in Appendix A.
Literature Review and Analysis
For the 2007 update, the expert panel completed the review and analysis of data published since 1999. Computerized literature searches of the PubMed database were performed. The searches of the English-language literature published from 1999 through July 2006 used the terms histoplasmosis and His810 CID 2007:45 (1 October) Wheat et al.
All members of the expert panel complied with the IDSA policy on conicts of interest, which requires disclosure of any nancial or other interest that might be construed as constituting an actual, potential, or apparent conict. Members of the expert panel were provided IDSAs conict of interest disclosure statement and were asked to identify ties to companies developing products that might be affected by promulgation of the guideline. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. The panel made decisions on a case-by-case basis as to whether
an individuals role should be limited as a result of a conict. Potential conicts are listed in the Acknowledgements section.
Revision Dates
At annual intervals, the Panel Chair, the SPGC liaison advisor, and the Chair of the SPGC will determine the need for revisions to the guideline on the basis of an examination of current literature. If necessary, the entire panel will be reconvened to discuss potential changes. When appropriate, the panel will recommend revision of the guideline to the SPGC and the IDSA Board for review and approval. RESULTS
Literature Search
The literature search identied 858 potential articles. A few abstracts from national meetings were included. The types of studies included randomized, clinical trials; open-label clinical trials; retrospective case series; case reports; reports of in vitro studies; and animal model experiments. Because of the limited nature of the data in many areas, the panel decided also to retain high-quality reviews or background papers. Panel members were assigned sections of the guideline and reviewed the relevant literature.
Limitations in the Literature
Review of the literature revealed a paucity of clinical trials evaluating the newer agents in histoplasmosis. Most data came from cohort studies; case series; small, nonrandomized clinical trials; or case reports.
Literature Search Results
Clinical manifestations. Severity of illness and disease manifestations after primary inhalation exposure to H. capsulatum vary, depending on the intensity of exposure and the immunity of the host. Acute exposure causes a spectrum of disease ranging from asymptomatic infection to severe pneumonitis with respiratory compromise. In most cases, illness resolves without therapy within 1 month [4]. Some patients, however, may experience protracted pulmonary complaints caused by persistent inammation of the lung or mediastinal lymph nodes. Acute pulmonary histoplasmosis also may be associated with other inammatory manifestations, including pericarditis and arthritis or arthralgia with erythema nodosum. Complications of pulmonary histoplasmosis include mediastinal lymphadenitis, mediastinal granuloma, chronic cavitary disease in patients with underlying emphysema, brosing mediastinitis, and broncholithiasis [4]. Hematogenous dissemination occurs in most patients during the rst few weeks after acute infection, but it is rarely progressive, resolving with the development of cell-mediated immunity to H. capsulatum. Progressive disseminated histoplas-
mosis occurs in individuals who are unable to mount a cell-mediated immune response to the organism and is fatal if untreated. Progressive disseminated histoplasmosis is dened as a clinical illness that does not improve after at least 3 weeks of observation and that is associated with physical or radiographic ndings and/or laboratory evidence of involvement of extrapulmonary tissues. Hepatosplenomegaly, mucosal ulcers and skin lesions, gastrointestinal involvement, pancytopenia, progressive elevation of hepatic enzyme levels, increased lactate dehydrogenase level, and increased serum ferritin level may provide clues to the diagnosis. Laboratory evidence of dissemination includes demonstration of granulomas with yeasts resembling H. capsulatum in extrapulmonary tissues, growth in culture of H. capsulatum, and persistent antigenuria and/or antigenemia. Chronic chorioretinitis, referred to as presumed ocular histoplasmosis syndrome, is commonly diagnosed in areas of endemicity [5], but it is not clearly caused by H. capsulatum. In one report, presumed ocular histoplasmosis was not responsive to amphotericin B treatment [6]. Treatment is clearly indicated in severe or moderately severe acute pulmonary, chronic pulmonary, disseminated, and CNS histoplasmosis (table 2). In other manifestations, the role of therapy is uncertain, and efcacy has not been assessed with clinical trials. Treatment is not indicated in asymptomatic patients with certain noninfectious complications or residue of healed histoplasmosis, such as asymptomatic pulmonary nodules, mediastinal lymphadenopathy, and splenic lesions, especially when calcied. Antifungal agents. The antifungal agents that have been proven to be effective and that are preferred for treatment of histoplasmosis include amphotericin B [7], liposomal amphotericin B [8], amphotericin B lipid complex [9], and itraconTable 2. Indications for antifungal therapy.
Denite indication, proven or probable efcacy Acute diffuse pulmonary infection, moderately severe symptoms, or severe symptoms Chronic cavitary pulmonary infection Progressive disseminated infection CNS infection Uncertain indication, unknown efcacy Acute focal pulmonary infection, asymptomatic case, or mild symptoms that persist for 11 month Mediastinal lymphadenitis Mediastinal granuloma Inammatory syndromes, treated with corticosteroids Not recommended, unknown efcacy or ineffective Mediastinal brosis Pulmonary nodule Broncholithiasis Presumed ocular histoplasmosis syndrome
azole [10, 11]. There is no evidence to recommend the echinocandins as treatment for histoplasmosis; in vitro susceptibility studies and animal experiments have shown conicting results [1214], and there is no published experience regarding treatment of humans who have histoplasmosis with echinocandins. Amphotericin B formulations are used for patients who have severe pulmonary or disseminated forms of histoplasmosis. A multicenter, randomized, blinded clinical trial demonstrated a higher response rate (88% vs. 64%) and lower mortality rate (2% vs. 13%) in patients who had AIDS and progressive disseminated histoplasmosis and who were treated with liposomal amphotericin B than among recipients of amphotericin B deoxycholate, respectively [8]. Amphotericin B lipid complex has also been used successfully for treatment of histoplasmosis [9] and may be preferred by some because of lower cost. Amphotericin B deoxycholate is the least expensive formulation and is a reasonable alternative to the lipid formulations for patients who are at a low risk for nephrotoxicity. Presently, except for children, for whom a 1-month course of amphotericin B deoxycholate is usually curative, it is rare to see amphotericin B given for the entire course of therapy, as was recommended in the 2000 guidelines. However, amphotericin B, as sole therapy, is effective and may be preferred in situations precluding treatment with itraconazole or other oral azoles. Generally, amphotericin B is used initially until the patient has shown a favorable response and can take an oral antifungal agent; then, itraconazole is given for the remainder of the treatment course. Itraconazole given orally is preferred for patients who have mild-to-moderate histoplasmosis and, as noted above, as stepdown therapy after the initial response to amphotericin B. The response rate for primary therapy with itraconazole in early studies was 100% for disseminated histoplasmosis and 80% for pulmonary histoplasmosis [10]. The oral capsule formulation or the solution can be used. Itraconazole capsules should be taken in the setting of high gastric acidity (concomitant consumption of food or a cola drink is recommended), to maximize absorption. In patients who are receiving antacids, H2 blockers, or proton pump inhibitors, the capsules should not be used because of decreased absorption. Itraconazole concentrations are higher with use of the solution given on an empty stomach than with capsules; thus, the solution should be used whenever possible. However, some patients dislike its taste or experience unacceptable gastrointestinal side effects, reducing adherence to therapy. Some patients are intolerant of itraconazole, are unable to achieve adequate blood levels with either preparation, or are receiving concomitant medications that lead to serious drug interactions with itraconazole. Thus, there is a need for alternative therapies. Fluconazole has been used successfully for treatment of histoplasmosis, but it appears to be less effective
than itraconazole. In patients with disseminated histoplasmosis who did not have AIDS, uconazole (200800 mg daily) was effective in 70% of cases [15]. Fluconazole (800 mg daily for 12 weeks as induction therapy, followed by 400 mg daily) [16] was less effective than itraconazole [11] for treatment of histoplasmosis in patients who had AIDS, and uconazole resistance developed in patients who failed therapy [17]. Ketoconazole is seldom used for histoplasmosis in the United States because of the increased number of adverse effects, compared with itraconazole. However, it is effective and much less expensive than itraconazole, justifying its use in some cases involving mild manifestations of histoplasmosis, but not in cases of disseminated or CNS disease. The newer azoles, posaconazole and voriconazole, also demonstrate in vitro activity against H. capsulatum [18]. Posaconazole appears to be more active in vitro [18] and in experimental infection [19]. Isolates that were noted to have become resistant to uconazole when patients with AIDS were treated with the agent were also noted to show increased MICs to voriconazole [18], suggesting that resistance may develop during treatment with voriconazole, as well as with uconazole [17]. Both voriconazole [2024] and posaconazole [2527] have been used successfully in a small number of patients with a variety of different forms of histoplasmosis. Data are inadequate to make an evidence-based recommendation, and all 4 of the other available azoles (i.e., uconazole, ketoconazole, voriconazole, and posaconazole) are second-line alternatives to itraconazole. The azoles exert their antifungal activity by inhibition of the fungal cytochrome P450 3A4-dependent enzyme lanosterol 14a-demethylase. The azoles vary in their ability to inhibit mammalian cytochrome P450 metabolism of other drugs, and several azoles (itraconazole and voriconazole) are extensively metabolized by hepatic cytochrome P450 enzymes. Thus, drugdrug interactions mediated through cytochrome P450 pathways are common and vary with each azole. In addition, posaconazole and itraconazole are both inhibitors and substrates of p-glycoprotein, and posaconazole is eliminated through glucuronidation, leading to other important drug-drug interactions. Up-to-date prescribing information should be reviewed before initiating azole therapy in patients who are taking other medications. The azoles may be hepatotoxic. Hepatic enzyme levels should be measured before therapy is started and at least at 1, 2, and 4 weeks and then every 3 months during therapy. Therapeutic drug monitoring. Optimization of itraconazole therapy for treatment of life-threatening systemic fungal infections is strongly recommended [28]. Blood concentrations vary widely in patients receiving itraconazole for treatment of histoplasmosis [11, 29]. Blood concentrations are 30% higher
using the solution formulation than the capsule formulation, but wide intersubject variability persists [30]. Itraconazole concentrations in serum should be determined only after steadystate has been reached, which takes 2 weeks. Serum levels should be obtained to ensure adequate absorption, to monitor changes in the dosage of itraconazole or the addition of interacting medications, to determine the cause of treatment failure, and to assess adherence. Because of its long half-life (24 h), blood concentrations of itraconazole vary little during a 24-h dosing interval. Thus, the timing of collection of the blood specimen in relationship to the most recent dose of itraconazole is not important. Histoplasma yeasts are highly susceptible to itraconazole, with MICs of !0.01 mg/mL in all strains tested. Although a blood concentration associated with treatment failure in histoplasmosis has not been identied, random concentrations of at least 1.0 mg/mL are recommended. Although the concentration associated with an increased risk for toxicity has not been dened, concentrations of 110 mg/mL are unnecessary for treatment of histoplasmosis, are likely to be associated with toxicity, and should prompt dosage reduction. When measured by high-pressure liquid chromatography, both itraconazole and its bioactve hydroxy-itraconazole metabolite are reported, the sum of which should be considered in assessing drug levels. Drug level monitoring is not recommended when using uconazole, because of its excellent drug exposure, even in patients with AIDS [16]. Although less information is available, therapeutic drug monitoring also appears to be appropriate when administering voriconazole [31] and posaconazole. Both agents demonstrate considerable subject-to-subject variability [3234] related to differences in absorption and/or metabolism. Furthermore, drug-drug interactions can lead to major changes in the serum concentrations of voriconazole [35]. Voriconazoles half-life is 68 h, and blood levels vary 2-fold over a 12h dosing interval [32]. Accordingly, timing of obtainment of the blood specimen in relationship to the most recent dose of the medication is essential in assessing voriconazole drug exposure. For voriconazole, the trough concentrations should be at least 0.5 mg/mL, and the peak concentration should be at least 2.0 mg/mL. Posaconazoles half-life is 12 h [33], and concentrations vary only slightly during a 1224-h dosing interval [33, 34]. Random concentrations of at least 0.5 mg/mL may be adequate. Voriconazole and posaconazole metabolites are not bioactive; thus, they are not reported by laboratories using high-pressure liquid chromatography. Azole blood levels are available in most of the large reference laboratories and several laboratories specializing in fungal diagnostics (e.g., Fungus Testing Laboratory [San Antonio, TX] and Mira Vista Diagnostics [Indianapolis, IN]). Use of antigen testing to monitor therapy for progressive disseminated histoplasmosis. Histoplasma antigen can be de-
tected in the urine in 190% of patients and in the serum in 80% of patients who have disseminated histoplasmosis, and this measurement is commonly used as an aid to early diagnosis (MiraVista Diagnostics) [36]. The sensitivity and specicity are increased in newer generations of the test [37, 38], but crossreactions occur in patients with other endemic mycoses [36, 39]. In patients with antigenuria and/or antigenemia, levels decrease during therapy [40] and increase in 90% of those who relapse [41]. Furthermore, failure of the antigen concentration to decrease may indicate treatment failure. Accordingly, changes in antigen levels can be used as indicators for response to therapy. Antigen levels should be measured before treatment is initiated, at 2 weeks, at 1 month, and then approximately every 3 months during therapy and for at least 6 months after treatment is stopped. Antigen levels also should be measured if treatment failure or relapse is suspected. In the experience of the panel, some patients have done well after receiving appropriate therapy when treatment was discontinued, despite having persistent low-level antigenuria. Also, in a study of withdrawal of suppressive therapy in patients with AIDS following immune reconstitution, none had relapse, even though 20% of patients had an antigen level of 13 U [42]. Considering the complexity of issues involved in decisions about discontinuation of therapy, the panel recommends that expert opinion be sought if the physician is uncertain whether to stop treatment because of persistent antigenuria. More specic guidance for use of antigen detection to monitor therapy is discussed in a recent review [36]. Salvage therapy in patients who fail standard therapy. The approach to therapy in patients who fail amphotericin B or itraconazole therapy is complex, and there are very limited data on which to make evidence-based recommendations. One study reported response to posaconazole in 3 patients who failed treatment with multiple drugs, including amphotericin B, itraconazole, and voriconazole, and in a fourth patient who failed itraconazole treatment [25]. Whether combining amphotericin B with an azole would be effective in refractory cases has not been reported. In animal models, however, the combination of amphotericin B and an azole was no more effective than amphotericin B alone [43, 44]; in fact, uconazole was antagonistic to amphotericin B. The role of immune modulator therapy in patients who fail antifungal therapy for histoplasmosis is unknown. Granulocytemacrophage colony-stimulating factor [45], IFN-g [46], and antibodies to H. capsulatum cell surface proteins [47] have demonstrated marginal benet in murine models but have not been studied in patients. A patient who had a specic defect in the IL-12/IFN-g pathway appeared to benet from IFN-g after antifungal therapy failed on several occasions [48]. The
panel recommends that expert opinion be sought in refractory cases. GUIDELINE RECOMMENDATIONS FOR THE TREATMENT OF HISTOPLASMOSIS The guideline recommendations are also summarized in table 3. WHAT IS THE TREATMENT FOR ACUTE AND CHRONIC PULMONARY HISTOPLASMOSIS?
Moderately Severe to Severe Acute Pulmonary Histoplasmosis
Recommendations 1. Lipid formulation of amphotericin B (3.05.0 mg/kg daily intravenously for 12 weeks) followed by itraconazole (200 mg 3 times daily for 3 days and then 200 mg twice daily, for a total of 12 weeks) is recommended (A-III). 2. The deoxycholate formulation of amphotericin B (0.7 1.0 mg/kg daily intravenously) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (A-III). 3. Methylprednisolone (0.51.0 mg/kg daily intravenously) during the rst 12 weeks of antifungal therapy is recommended for patients who develop respiratory complications, including hypoxemia or signicant respiratory distress (B-III). Evidence summary. The effectiveness of therapy in patients with acute pulmonary histoplasmosis is based on anecdotal case reports, as recently summarized elsewhere [36], and clinical experience. In severe cases, cases accompanied by respiratory insufciency, or hypoxemia, anecdotal reports [49] suggest that corticosteroid therapy may hasten recovery. In most patients for whom corticosteroids are considered, hospitalization is appropriate. The optimal duration of therapy is unknown, but presumably a relatively short course of 12 weeks may sufce, because cell-mediated immunity to Histoplasma usually develops within the rst month of infection. The pulmonary inltrates should be resolved on the chest radiograph before antifungal therapy is stopped.
Mild-to-Moderate Acute Pulmonary Histoplasmosis
patients were hospitalized. In a more recent outbreak at a high school, only 3.7% of patients received antifungal therapy, and only 2.5% of children, several of whom were immunocompromised, were hospitalized [51]. However, whether therapy could hasten recovery in such cases is unknown, because clinical trials of treatment for acute pulmonary histoplasmosis have not been conducted. Antifungal treatment has been recommended in patients whose symptoms do not improve within 1 month [52], but no clinical trials have been performed to prove efcacy in this situation. In such cases, persistent fever, fatigue, or weight loss raises concern about the development of progressive disseminated histoplasmosis, providing an additional reason for the initiation of antifungal therapy. If treatment is administered, a 612-week course of itraconazole (200 mg once or twice daily) is recommended. In an open-label clinical trial, a small number of patients who had persistent symptomatic pulmonary histoplasmosis were shown to respond to itraconazole (200 mg once or twice daily, given for at least 6 months) [10].
Chronic Cavitary Pulmonary Histoplasmosis
Recommendations 5. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for at least 1 year) is recommended, but some prefer 1824 months in view of the risk for relapse (A-II). 6. Blood levels of itraconazole should be obtained after the patient has been receiving this agent for at least 2 weeks to ensure adequate drug exposure (A-III). Evidence summary. Patients with underlying emphysema often develop progressive pulmonary disease, which is characterized by cavities with surrounding inammation, after infection with H. capsulatum [4]. The effectiveness of therapy with either amphotericin B or itraconazole for chronic pulmonary histoplasmosis has been established by clinical trials and cohort studies [10, 5357]. Relapses have occurred in 9%15% of those treated with these agents. Treatment should be continued until pulmonary imaging shows no further improvement when monitored at 46-month intervals. In most cases, chest radiographs provide sufcient information for monitoring response to therapy. Patients should continue to be monitored for relapse for at least 1 year after they stop itraconazole treatment. Results of tests for detection of antigen are usually negative in patients with chronic pulmonary histoplasmosis and play a limited role in an assessment of response to treatment. Furthermore, although antibody levels generally decrease with recovery, insufcient data are available to support measurement of antibody levels for assessment of response to treatment.
Recommendation 4. Treatment is usually unnecessary (A-III). Itraconazole (200 mg 3 times daily for 3 days and then 200 mg once or twice daily for 612 weeks) is recommended for patients who continue to have symptoms for 11 month (B-III). Evidence summary. Antifungal treatment is unnecessary in patients with mild symptoms caused by acute pulmonary histoplasmosis. In an outbreak in a junior high school [50], illness resolved within 3 weeks in 195% of cases, and only 1% of
WHAT IS THE TREATMENT FOR THE COMPLICATIONS FROM PULMONARY HISTOPLASMOSIS (E.G., PERICARDITIS, ARTHRITIS/ERYTHEMA NODOSUM, MEDIASTINAL LYMPHADENITIS, MEDIASTINAL GRANULOMA, MEDIASTINAL FIBROSIS, BRONCHOLITHIASIS, AND PULMONARY NODULE)?
Pericarditis
Recommendations 7. Nonsteroidal anti-inammatory therapy is recommended in mild cases (B-III). 8. Prednisone (0.51.0 mg/kg daily [maximum, 80 mg daily] in tapering doses over 12 weeks) is recommended for patients with evidence of hemodynamic compromise or unremitting symptoms after several days of therapy with nonsteroidal anti-inammatory therapy (B-III). 9. Pericardial uid removal is indicated for patients with hemodynamic compromise (A-III). 10. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for 612 weeks) is recommended if corticosteroids are administered (B-III). Evidence summary. Pericarditis occurs as a complication of inammation in adjacent mediastinal lymph nodes in patients with acute pulmonary histoplasmosis. It represents an inammatory condition rather than infection of the pericardium. Pericardial infection is a very rare complication of disseminated disease. Patients respond to nonsteroidal anti-inammatory agents without antifungal therapy, often improving after only a few days of therapy [58, 59]. Large pericardial effusions may impair cardiac output, however, and thus require drainage [59]. Pericardial constriction is rare and is not a basis for prophylactic therapy or surgical removal of the pericardium. If corticosteroids are used, concurrent itraconazole treatment is recommended to reduce the risk of progressive infection. If the patient has symptomatic acute pulmonary histoplasmosis with features for which treatment is recommended, in addition to pericarditis, itraconazole therapy is appropriate
Rheumatologic Syndromes
Evidence summary. Arthritis or arthralgia with erythema nodosum occurs in 5%10% of cases as a systemic inammatory response to acute pulmonary histoplasmosis [60, 61]. These manifestations do not represent infection, and they respond to nonsteroidal anti-inammatory agents without antifungal therapy. In some cases, the manifestations are moderately severe, requiring treatment with corticosteroids [60]. If corticosteroids are used, concurrent itraconazole treatment is recommended to reduce the risk of progressive infection. Bone or joint involvement is very rare in progressive disseminated histoplasmosis, but it should not be overlooked.
Mediastinal Lymphadenitis
Recommendations 14. Treatment is usually unnecessary (A-III). 15. Itraconazole (200 mg 3 times daily for 3 days and then 200 mg once or twice daily for 612 weeks) is recommended in patients who have symptoms that warrant treatment with corticosteroids and in those who continue to have symptoms for 11 month (B-III). 16. Prednisone (0.51.0 mg/kg daily [maximum, 80 mg daily] in tapering doses over 12 weeks) is recommended in severe cases with obstruction or compression of contiguous structures (B-III). Evidence summary. Antifungal treatment is unnecessary in most patients with symptoms due to mediastinal lymphadenitis. The symptoms that occur most frequently are chest pain, cough and/or atelectasis due to bronchial compression, or dysphagia resulting from esophageal compression. Children are more likely than adults to present with airway obstruction. In patients with symptoms of compression of the airways or esophagus, administration of prednisone in tapering doses over 12 weeks may result in prompt relief by reducing the size of the inamed lymph nodes [62]. Itraconazole is recommended for 612 weeks to reduce the risk of progressive disseminated disease caused by corticosteroid-induced immunosuppression in patients who are given corticosteroids and in patients whose symptoms last longer than 1 month.
Mediastinal Granuloma
Recommendations 11. Nonsteroidal anti-inammatory therapy is recommended in mild cases (B-III). 12. Prednisone (0.51.0 mg/kg daily [maximum, 80 mg daily] in tapering doses over 12 weeks) is recommended in severe cases (B-III). 13. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for 612 weeks) is recommended only if corticosteroids are administered (B-III).
Recommendations 17. Treatment is usually unnecessary (A-III) 18. Itraconazole (200 mg 3 times daily for 3 days and then once or twice daily for 612 weeks) is recommended for symptomatic cases (B-III). Evidence summary. The term mediastinal granuloma describes a large (310 cm in adults but smaller in children), mostly caseous mass of mediastinal lymph nodes that coalesce into a single encapsulated lesion, which is usually located in
Table 3.
Treatment Lipid AmB (3.05.0 mg/kg daily) or deoxycholate AmB (0.71.0 b mg/kg daily) for 12 weeks, followed by Itra (200 mg twice daily for a total of 12 weeks) A-III B-III A-III B-III A-II B-III B-III B-III B-III A-III B-III
a
Recommendations for the treatment of histoplasmosis.

Class Comments Usually follows easily identiable heavy exposure and is accompanied by diffuse inltrates and hypoxemia Effectiveness is not well documented Whether treatment shortens the duration of illness is unknown
Manifestation
Acute pulmonary histoplasmosis
Moderately severe or severe
Mild to moderate
816 Nonsteroidal anti-inammatory agents Nonsteroidal anti-inammatory agents Mild symptoms of !4 weeks, none Symptoms warranting treatment with prednisone, prednisone (0.51.0 mg/kg daily in tapering doses over 12 weeks) and Itra (200 mg once or twice daily for 612 weeks) Symptoms of 14 weeks, Itra (200 mg once or twice daily for 612 weeks) Asymptomatic, none Symptomatic, Itra (200 mg once or twice daily for 612 weeks) Antifungal treatment not indicated Stenting of obstructed vessels can be useful Itra (200 mg once or twice daily for 612 weeks)
Methylprednisolone (0.51.0 mg/kg daily intravenously for 12 weeks) For symptoms of !4 weeks, none For symptoms of 14 weeks, Itra (200 mg once or twice daily for 612 weeks)
Relapse occurs in 15% of cases Tamponade requires drainage of pericardial uid; antifungal therapy is given to reduce possible dissemination caused by prednisoneinduced immunosuppression
Chronic cavitary pulmonary histoplasmosis Itrab (200 mg once or twice daily for at least 12 months) Pericarditis Moderately severe to severe Itra (200 mg once or twice daily for 612 weeks) only if prednisone used Prednisone (0.51.0 mg/kg daily in tapering doses over 12 weeks)
Mild
Rheumatologic histoplasmosis
Usually rapidly effective at reducing symptoms and pericardial effusion Corticosteroids are rarely needed Nonsteroidal anti-inammatory agents may be given, but the effectiveness is unknown; corticosteroids are rarely needed but have been used in severe cases involving airway obstruction B-III B-III B-III A-III B-III C-III Surgery may be required to relieve obstruction Surgery should be avoided Surgery should be avoided Treatment given only if clinical ndings cannot differentiate mediastinal brosis from mediastinal granuloma
Mediastinal lymphadenitis
Mediastinal granuloma
Mediastinal brosis
Broncholithiasis Pulmonary nodule Progressive disseminated histoplasmosis Liposomal AmBa (3.0 mg/kg daily), AmB lipid complexa (5.0 mg/kg a daily), or deoxycholate AmB (0.71.0 mg/kg daily) for 12 weeks, followed by Itraa (200 mg twice daily for at least 12 months) A-I Itra (200 mg twice daily for at least 12 months) Liposomal AmBa (5.0 mg/kg daily for 46 weeks), followed by Itrab (200 mg 23 times daily for at least 12 months) B-III A-II Longer treatment may be required in patients with persistent c immunodeciency
None None
A-III A-III
Removal of stones by bronchoscopy or surgery may be indicated Must be differentiated from malignancy
Moderately severe to severe
Mild to moderate
CNS histoplasmosis
Longer treatment may be required in patients with persistent c immunodeciency High failure and relapse rates support aggressive therapy, but whether less intensive therapy would sufce is unknown; longer treatment may be required for patients with persistent immunodeciencyc
NOTE. AmB, amphotericin B; Itra, itraconazole. With regard to prophylaxis, there are few studies on which to make evidence-based recommendations on the role of prophylaxis to prevent histoplasmosis in immunosuppressed patients. Prophylaxis is not used routinely but is reserved for situations in which the rate of development of infection exceeds 10 cases per 100 patient-years. The optimal duration for prophylaxis is unknown, but health care providers should consider the incidence of histoplasmosis in the community and the severity of immunosuppression. Itra (200 mg daily) is recommended when prophylaxis is prescribed. With regard to pregnancy, all azoles are contraindicated because of the risk of teratogenicity. Otherwise, the indications for treatment are not different in pregnancy, and lipid formulations of AmB are preferred. AmB deoxycholate is preferred for use in children, because it is effective, well tolerated, and less costly. The dosage of Itra for children is 5.010.0 mg/kg daily in 2 divided doses, not to exceed 400 mg daily. The dosage of methyl-prednisolone is 2.0 mg/kg daily given intravenously, and the dosage of prednisone is 2.0 mg/kg daily given orally. Indomethacin (1.03.0 mg/kg daily, divided 3 times) is the nonsteroidal antiinammatory agent of choice for pericarditis in children.
817
Liposomal AmB (3.0 mg/kg daily) or AmB lipid complex (5.0 mg/kg daily) are recommended for 12 weeks, except in patients with meningitis, for whom the dosage of liposomal AmB is 5.0 mg/kg daily for 4 6 weeks. The deoxycholate formulation of AmB (0.71.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity. b Itra should be given as a loading dose of 200 mg 3 times daily for the rst 3 days, followed by 200 mg twice daily thereafter. Itra (200 mg once daily) may be sufcient in patients with less severe manifestations of histoplasmosis. If used for prophylaxis, a dosage of 200 mg daily is recommended. Concentrations of Itra in serum should be monitored in patients being treated for chronic pulmonary, disseminated, or CNS histoplasmosis; a random serum concentration 11.0 mg/mL should be sought. Drug monitoring is infrequently needed for patients receiving shorter courses of therapy for acute pulmonary histoplasmosis and its complications. c Chronic, potentially lifelong suppressive therapy with Itra is required for patients with AIDS who do not achieve immune reconstitution in response to antiretroviral therapy. Lifelong suppressive therapy may be useful in patients with other immunosuppressive disorders in whom immunosuppression cannot be substantially reduced and in patients who experience relapse despite receipt of appropriate therapy.
the right paratracheal region or the subcarinal area [52, 63]. Most patients are asymptomatic, and mediastinal granuloma is found incidentally by imaging studies, but symptoms related to compression of adjacent structures can occur. The caseous center can spontaneously drain via a stula or sinus tract to the bronchus, skin, or esophagus; bacterial superinfection occasionally develops when stulae or sinus tracts are present [64]. Itraconazole is appropriate for symptomatic cases, but there are no controlled trials to prove its efcacy. The capsule is thin (23 mm) and adherent, but it is not invasive, so surgical removal or decompression with removal of the free wall and contents is possible when involvement of the superior vena cava or esophagus causes persistent symptoms (despite administration of antifungal therapy). There is no evidence that mediastinal granuloma evolves into mediastinal brosis. Thus, treatment with either surgery or itraconazole should not be used to prevent the development of mediastinal brosis [63, 64].
Mediastinal Fibrosis
antifungal therapy. Corticosteroid therapy has not been helpful when tried [66, 71, 72] and is discouraged. Placement of intravascular stents has been helpful in some patients with superior vena cava, pulmonary artery, or pulmonary vein obstruction [73] and should be considered especially for patients who are at highest risk because of involvement of both lungs. The placement of stents in obstructed airways is not recommended because of the high risk of growth of granulation tissue, leading to recurrent obstruction, but it may be necessary in selected patients in whom interventional airway experts nd that no other treatment alternative is feasible. Surgery should be approached with great caution in patients with mediastinal brosis and should be performed only for those who are expected to die of the condition without intervention. Surgeons experienced in the management of this condition should be consulted [72].
Broncholithiasis
Recommendations 19. Antifungal treatment is not recommended (A-III). 20. The placement of intravascular stents is recommended for selected patients with pulmonary vessel obstruction (B-III). 21. Itraconazole (200 mg once or twice daily for 12 weeks) is recommended if clinical ndings cannot differentiate mediastinal brosis from mediastinal granuloma (C-III). Evidence summary. Mediastinal brosis is characterized by invasive brosis that encases mediastinal or hilar nodes and that is dened by occlusion of central vessels and airways [65 68]. Occlusion of airways or vessels of both lungs occurs in only a small proportion of cases (20%) but is usually fatal [69]. Most patients have occlusion of the superior vena cava or loss of function of only 1 lung, which may have signicant morbidity with chest pain or hemoptysis, but long-term survival is generally favorable [69]. Most authorities believe that neither antifungal nor antiinammatory treatment ameliorates the outcome of mediastinal brosis [65, 66], but others have reported improvement after antifungal therapy [70]. If the clinical ndings are consistent with a more inammatory process rather than a chronic brotic process, especially if complement xation antibodies for H. capsulatum are present and the erythrocyte sedimentation rate is elevated, treatment should be considered. A 12week course of itraconazole (200 mg once or twice daily) is suggested if clinical and CT ndings do not differentiate mediastinal brosis from mediastinal granuloma. Patients who truly have mediastinal brosis are not expected to respond to
Recommendations 22. Antifungal treatment is not recommended (A-III). 23. Bronchoscopic or surgical removal of the broncholith is recommended (A-III). Evidence summary. Broncholithiasis is the erosion of calcied lymph nodes into a bronchus, often causing hemoptysis and inammation. Spitting of small pieces of white chalk-like material, termed lithoptysis, may occur [52]. When stones of substantial size are extruded, they may cause prolonged periods of intense cough and hemoptysis, with localized wheeze and distal obstructive pneumonitis. Diagnosis is made bronchoscopically. Removal of the stones bronchoscopically or surgically is recommended.
Pulmonary Nodules (Histoplasmomas)
Recommendation 24. Antifungal treatment is not recommended (A-III). Evidence summary. Lung parenchymal sites of infection may contract and then persist indenitely as lung nodules or histoplasmomas [74]. Calcication is usually found in the center of a histoplasmoma or in concentric rings and is generally diagnostic, although it may require years to develop and is not always present. Histoplasmomas may enlarge slowly and even cavitate [74]. Pulmonary nodules cause no symptoms, usually are identied as incidental ndings on chest radiographs or CTs, and are frequently removed surgically to exclude malignancy. There is no evidence that antifungal agents have any effect on histoplasmomas or that histoplasmomas contain viable organisms. This recommendation applies to patients who are asymptomatic and who have 1 or a few isolated nodules.
This recommendation does not apply to symptomatic patients who have multiple or diffuse nodules, which may represent acute pulmonary histoplasmosis. WHAT IS THE TREATMENT FOR PROGRESSIVE DISSEMINATED HISTOPLASMOSIS?
Recommendations 25. For moderately severe to severe disease, liposomal amphotericin B (3.0 mg/kg daily) is recommended for 12 weeks, followed by oral itraconazole (200 mg 3 times daily for 3 days and then 200 mg twice daily for a total of at least 12 months) (A-I). 26. Substitution of another lipid formulation at a dosage of 5.0 mg/kg daily may be preferred in some patients because of cost or tolerability (A-III). 27. The deoxycholate formulation of amphotericin B (0.71.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (A-III). 28. For mild-to-moderate disease, itraconazole (200 mg 3 times daily for 3 days and then twice daily for at least 12 months) is recommended (A-II). 29. Lifelong suppressive therapy with itraconazole (200 mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed (A-II) and in patients who relapse despite receipt of appropriate therapy (C-III). 30. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (B-III). 31. Antigen levels should be measured during therapy and for 12 months after therapy is ended to monitor for relapse (B-III). Persistent low-level antigenuria may not be a reason to prolong treatment in patients who have completed appropriate therapy and have no evidence of active infection. Evidence summary. Progressive disseminated histoplasmosis is fatal without therapy [54], and treatment with either amphotericin B [7, 8, 54] or itraconazole [10, 11] is highly effective. Among patients with AIDS and moderately severe to severe disseminated histoplasmosis, the rate of response was higher (88% vs. 64%) and the mortality rate was lower (2% vs. 13%) among recipients of liposomal amphotericin B (3 mg/kg daily for 12 weeks) than among recipients of the deoxycholate formulation [8]. In patients with severe disease, renal impairment is common as a consequence of multiple-organ failure caused by severe histoplasmosis or amphotericin B nephrotoxicity. Often, physicians consider switching to an azole in such cases, to avoid further renal impairment. The panel recommends continued treatment with liposomal amphotericin B. The poor prognosis justies using the most effective therapy, despite nephrotoxicity. In many cases, renal impairment improves despite continued
receipt of amphotericin B as a result of improvement in the patients overall condition. Although it was recommended in the 2000 guidelines on the basis of the results of earlier studies [7, 54], therapy with amphotericin B for the entire therapeutic course (typically 35 mg/ kg given over 48 weeks) is now uncommon. Step-down therapy to oral itraconazole has become the standard of practice and is supported by studies of patients with AIDS [8]. Response rates of 80%100% were reported using itraconazole for treatment of disseminated histoplasmosis in patients who were not severely ill and who did not have CNS involvement [10, 11]. Itraconazole is administered at 200 mg 3 times daily for 3 days as a loading dose, followed by 200 mg twice daily [10, 11], as guided by determination of the blood concentration of itraconazole, for at least 1 year. In immunosuppressed patients, an even longer course of therapy should be considered. Treatment should be continued until clinical and laboratory ndings have returned to normal. Ten percent to 15% of patients experience relapse [10, 11], which may be a basis for long-term maintenance therapy. In patients with AIDS, the timing of antiretroviral therapy poses an interesting dilemma. Antiretroviral therapy causes improvement in cellular immunity, the key defense against H. capsulatum. Not surprisingly, the outcome of disseminated histoplasmosis is better in patients receiving antiretroviral therapy. In a recent report, the response rate was 100% among patients receiving antiretroviral therapy, compared with 47% among those who were not treated with antiretroviral therapy [75]. Initiation of antiretroviral therapy may unmask undiagnosed histoplasmosis through immune reconstitutioninduced inammation [76, 77]. Immune reconstitution inammatory syndrome during treatment for histoplasmosis is rare, however, and the clinical manifestations are usually not severe [76]. Accordingly, antiretroviral therapy should not be withheld on the basis of concern about the possible development of immune reconstitution inammatory syndrome. Long-term suppressive therapy with itraconazole [29] was recommended previously for patients with AIDS [1]. Subsequently, studies have shown that itraconazole can be safely discontinued in patients who have a good immunologic response to antiretroviral therapy [42]. For consideration of discontinuation of suppressive therapy, data suggest that patients should have received at least 1 year of itraconazole therapy, should have negative results of blood cultures, should have a Histoplasma serum and urine antigen level !2 ng/mL (comparable to 4 U/mL in the original assay) and a CD4 T cell count 1150 cells/mm3, and should be receiving HAART [42]. Although the practice of discontinuation of suppressive therapy in patients with AIDS who have good immunologic recovery is widespread, the number of published trials evaluating this strategy is small.
Suppressive therapy should be resumed if patients become nonadherent with antiretroviral therapy, if antiretroviral therapy is failing, or if the CD4 T cell count decreases to !150 cells/mm3. Suppressive therapy also may be warranted in patients with other immunodecient states that cannot be reversed, but there are no data and minimal clinical experience on which to base this recommendation. IS PROPHYLAXIS RECOMMENDED FOR IMMUNOSUPPRESSED PATIENTS? Recommendations 32. Prophylaxis with itraconazole (200 mg daily) is recommended in patients with HIV infection with CD4 cell counts !150 cells/mm3 in specic areas of endemicity where the incidence of histoplasmosis is 110 cases per 100 patient-years (A-I). 33. Prophylaxis with itraconazole (200 mg daily) may be appropriate in specic circumstances in other immunosuppressed patients (C-III). Evidence summary. There are few studies on which to make evidence-based recommendations on the role of prophylaxis to prevent histoplasmosis in immunosuppressed patients: a single study has addressed this issue in patients with AIDS. Itraconazole (200 mg daily) prevented histoplasmosis in patients with HIV infection who had CD4 cell counts !150 cells/mm3 and who lived in an area of hyperendemicity [78]. Prophylaxis had no impact on survival, however. Accordingly, prophylaxis is not used routinely but is reserved for situations in which the rate of development of infection exceeds 10 cases per 100 patientyears. The duration of prophylaxis has not been studied. On the basis of studies showing that suppressive therapy for disseminated histoplasmosis in AIDS can be stopped in patients whose CD4 cell count increases to 150 cells/mm3 [42], continuation of itraconazole as long as the incidence of histoplasmosis exceeds the threshold noted above and the CD4 count is !150 cells/mm3 seems to be prudent. The optimal duration for prophylaxis in patients with immunosuppressive conditions other than AIDS is unknown, and health care providers should consider the incidence of histoplasmosis in the community and the severity of immunosuppression. Today, a more common question is the need for prophylaxis in a patient who is receiving immunosuppressive therapy for malignancy, organ transplantation, or chronic inammatory disease and who exhibits radiographic or serologic evidence of past histoplasmosis. The utility of prophylaxis in these patients has not been studied, but the risk of histoplasmosis appears to be low. Histoplasmosis was not observed after a mean of 16 months of follow-up in 1500 patients who received immunosuppressive therapy for solid organ or bone marrow transplantation in an area of hyperendemicity [79]. Included in this
study were persons with radiographic (calcied lung or spleen lesions) or serologic (complement xation titers of 1:8 or 1: 16 or M band by immunodiffusion) evidence of old histoplasmosis, none of whom developed active histoplasmosis. On the other hand, therapy with TNF antagonists has been noted to be a risk factor for the development of disseminated histoplasmosis; in fact, histoplasmosis is the most common fungal infection associated with TNF antagonist therapy [80]. Active histoplasmosis during the past 2 years may be a basis for itraconazole prophylaxis during immunosuppression. Evidence of recent histoplasmosis includes a history of pulmonary infection, with radiographic ndings showing inltrates, nodules, or lymphadenopathy without a clear etiology; Histoplasma antigenuria; or anti-Histoplasma complement xation antibody titers 1:32. The appropriate duration of prophylaxis is unknown. In patients who have nished treatment for histoplasmosis and who are about to receive a transplant or to commence new immunosuppressive therapies, a urinary antigen level should be obtained before the new intervention and then every 23 months during the intensive course of immunosuppression. An increase in urinary antigen levels should be assessed with a more thorough investigation for active histoplasmosis, including chest CT and bronchoscopy (if inltrates are identied), blood cultures using methods suitable for isolation of Histoplasma species, and a careful search for disseminated histoplasmosis. A consistent elevation of the urinary Histoplasma antigen level should prompt initiation of antifungal therapy empirically in the context of ongoing immunosuppression. WHAT IS THE TREATMENT FOR CNS HISTOPLASMOSIS? Recommendations 34. Liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 46 weeks) followed by itraconazole (200 mg 2 or 3 times daily) for at least 1 year and until resolution of CSF abnormalities, including Histoplasma antigen levels, is recommended (B-III). 35. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (B-III). Evidence summary. CNS histoplasmosis includes meningitis, parenchymal lesions of the brain and/or spinal cord, or both. The response to therapy is inferior to that in other types of histoplasmosis [81]; thus, an aggressive approach is recommended [82]. In a recent review of experience in one medical center, 4 of 5 patients treated with amphotericin B (40 mg/kg over 8 weeks) followed by uconazole (200400 mg daily for 12 months) made a full recovery, and the fth had minor sequelae [83]. The panel preferred a high dose (5 mg/kg daily) of liposomal amphotericin B rather than amphotericin B lipid
complex in adults, in part because liposomal amphotericin B achieves the highest concentrations in brain tissue [84]. However, they also noted that there are no data to specically support this recommendation for CNS Histoplasma infection. Of note is the fact that none of the amphotericin B formulations achieve detectable concentrations in CSF. Some have reported success with a shorter course of amphotericin B (23 weeks) followed by an azole [8589], but the panel recommended a longer course of liposomal amphotericin B therapy. After completion of 46 weeks of treatment with liposomal amphotericin B, itraconazole is recommended for at least 1 year. Although itraconazole does not achieve detectable levels in CSF, it was more effective than uconazole in an animal model of CNS histoplasmosis [43]. The role of combination therapy has not been studied in humans. In the animal model, however, uconazole was antagonistic to amphotericin B, and the addition of itraconazole to the amphotericin B regimen failed to improve the outcome noted with amphotericin B alone [43]. Therefore, combination treatment is not recommended. Whether an azole alone would be effective treatment is not known. Itraconazole was as effective as amphotericin B in an animal model of CNS histoplasmosis [43]. Also, individual cases have been reported in which patients responded to azoles without having received prior amphotericin B treatment; these azoles include ketoconazole [90], itraconazole [83, 91], uconazole [83, 92], uconazole combined with itraconazole [83], and voriconazole [24]. Another report described a patient for whom multiple prior regimens had failed but who had responded to posaconazole treatment [25]. However, the panel felt that the evidence was insufcient to recommend azole therapy alone for CNS histoplasmosis. Although resection of brain or spinal cord lesions has been reported, surgery is rarely needed and should be performed only with progressive clinical ndings despite receipt of antifungal therapy. WHAT IS THE TREATMENT FOR HISTOPLASMOSIS IN PREGNANCY? Recommendations 36. Lipid formulation amphotericin B (3.05.0 mg/kg daily for 46 weeks) is recommended (A-III). 37. The deoxycholate formulation of amphotericin B (0.71.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (A-III). 38. If the newborn shows evidence for infection, treatment is recommended with amphotericin B deoxycholate (1.0 mg/kg daily for 4 weeks) (A-III). Evidence summary. Unique issues in pregnancy include the risk of teratogenic complications of azole therapy [93] and of transplacental transmission of H. capsulatum to the fetus [94].
Transplacental transmission may be prevented by administration of antifungal therapy before delivery, but the evidence is not adequate to make a recommendation. The placenta should be examined histopathologically for granuloma and for organisms resembling H. capsulatum. Furthermore, the baby should be monitored for clinical and laboratory ndings suggestive of histoplasmosis, in which case treatment with amphotericin B deoxycholate is recommended. Amphotericin B remains the treatment of choice in pregnancy, and the lipid formulations are safe [93]. The azoles are teratogenic and embryotoxic in animals and should be avoided during pregnancy. Long-term administration of uconazole during pregnancy has been associated with congenital anomalies [95]. Women of childbearing age who receive azole antifungal agents should use effective contraception during therapy and for 2 months after it is stopped. Reports suggesting that fetal risk is not increased [9698] focused on low-dose, short-duration therapy and should not be used as a basis for azole treatment for histoplasmosis. Theoretically, the risk for toxicity during the third trimester may be low, but there are no data available to assess the safety of prolonged treatment for histoplasmosis. WHAT TREATMENT IS RECOMMENDED FOR HISTOPLASMOSIS IN CHILDREN? Symptoms of histoplasmosis in children are similar to those that occur in adults, with some exceptions. Acute pulmonary manifestations are common; however, chronic pulmonary infection has not been described. Airway obstruction caused by mediastinal lymphadenitis is more common in children than in adults because of greater airway pliability in children. Lithoptysis and broncholithiasis are rarely seen. Rheumatologic complications are similar, although erythema nodosum is unusual and is almost never associated with arthritis or arthralgia. Mediastinal brosis rarely occurs during childhood. Meningitis is common in progressive disseminated histoplasmosis of infancy [99], but the subacute meningitis and parenchymal lesions characteristic of CNS infections in adults are rarely seen in children. The recommendations for management of progressive disseminated histoplasmosisthe most common reason for treatment in childrenwill be reviewed in more detail.
Acute Pulmonary Histoplasmosis
Recommendations 39. Treatment indications and regimens are similar to those for adults, except that amphotericin B deoxycholate (1.0 mg/kg daily) is usually well tolerated, and the lipid preparations are not preferred (A-III). 40. Itraconazole dosage in children is 5.010.0 mg/kg daily
in 2 divided doses (not to exceed 400 mg daily), generally using the solution formulation (A-III).
Progressive Disseminated Histoplasmosis
Recommendations 41. Amphotericin B deoxycholate (1.0 mg/kg daily for 4 6 weeks) is recommended (A-III). 42. Amphotericin B deoxycholate (1.0 mg/kg daily for 2 4 weeks) followed by itraconazole (5.010.0 mg/kg daily in 2 divided doses) to complete 3 months of therapy is an alternative (A-III). 43. Longer therapy may be needed for patients with severe disease, immunosuppression, or primary immunodeciency syndromes (A-III). 44. Lifelong suppressive therapy with itraconazole (5.0 mg/kg daily, up to 200 mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed (A-II) and in patients who experience relapse despite receipt of appropriate therapy (C-III). 45. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (B-III). 46. Antigen levels should be monitored during therapy and for 12 months after therapy is ended to monitor for relapse (B-III). Persistent low-level antigenuria may not be a reason to prolong treatment in patients who have completed appropriate therapy and have no evidence of active infection. Evidence summary. Progressive disseminated infection, often accompanied by meningitis [99], may occur in otherwise healthy infants aged !2 years, presumably resulting from relatively immature cellular immunity. Most are ultimately found to be immunologically healthy. Additional risk factors for disseminated histoplasmosis at any age include large inoculum exposure and acquired immunodeciency resulting from use of immunosuppressive agents, malnutrition, or HIV infection. Primary immunodeciency disorders that impair the function of T cells, monocytes, and macrophages also predispose to disseminated histoplasmosis. Progressive disseminated histoplasmosis in children is fatal if untreated [100]. Amphotericin B deoxycholate (1 mg/kg daily) given for 4 weeks has been used successfully [100103] and with minimal toxicity. A lipid formulation of amphotericin B (35 mg/kg daily) may be substituted if the patient is intolerant of amphotericin B deoxycholate. A shorter course of amphotericin B followed by an azole was effective in 74% of cases [101] and is an alternative to a prolonged course of amphotericin B treatment. In contrast to cases in adults, meningitis that accompanies progressive disseminated histoplasmosis of infancy responds to amphotericin B deoxycholate (given for 46 weeks) without a high rate of relapse [99]. Treatment recommended for progressive disseminated histoplasmosis of infancy does not need
to be modied in patients found to have CNS involvement. In a single report, amphotericin B (1 mg/kg daily for 40 days) followed by ketoconazole for 3 months was successful in 88% of cases [99]. The panel favored itraconazole (10 mg/kg daily) in place of ketoconazole, however. Prolonged treatment with amphotericin B may be needed for patients with large fungal burdens, particularly infants who present with prolonged failure to thrive, pancytopenia, coagulopathy, gastrointestinal ulceration, and meningitis and in severely affected patients who have received TNF antagonist therapy or who have congenital immunodeciencies that cannot be reversed. Less severe infection can be treated with a 2 4-week course of amphotericin B followed by itraconazole for a total duration of therapy of 3 months in families judged to be compliant with oral therapy. Experience using itraconazole as sole treatment for progressive disseminated histoplasmosis in infants and older children is limited. In a report of seven children (mean age, 4.6 years) with disseminated histoplasmosis treated with only itraconazole for 312 months, 5 were markedly improved at the conclusion of 36 months of treatment, and none experienced relapse [104]. One child died 1 month after treatment was stopped. The use of itraconazole as sole treatment of disseminated histoplasmosis is not recommended. However, in infrequent situations, in which the child has only mild-to-moderate symptoms, itraconazole may be considered as primary therapy if the clinical course and laboratory ndings are closely monitored. Candidates for oral itraconazole should include those in whom compliance is expected and absorption of the drug is assured. Children with disseminated histoplasmosis and HIV infection can be treated with the protocol recommended for adults, using dosages appropriate for children. Children with disseminated histoplasmosis should be screened for HIV infection. Low CD4 cell counts are common during the acute phase of disseminated histoplasmosis in infancy [99, 105], and assessment of cellular immunity later in the course is needed to exclude primary immunodeciency. Antigen testing, as described in the section on adults, should be used to monitor the effectiveness of therapy. The blood antigen level decreases rapidly (within 2 weeks), whereas the urine antigen level may decrease more slowly and may persist in low concentrations for several months before antigenuria fully resolves [102]. PERFORMANCE MEASURES
1. Itraconazole is the preferred azole for initial therapy for patients with mild-to-moderate histoplasmosis and as stepdown therapy after receipt of amphotericin B. When other azole agents are used, the medical record should document the specic reasons that itraconazole was not used and why other azoles were used.
2. Patients with severe or moderately severe histoplasmosis should be treated with an amphotericin B formulation initially. When amphotericin B is used, the patients electrolyte level, renal function, and blood cell count should be monitored several times per week and documented in the medical record. 3. Itraconazole drug levels should be measured during the rst month in patients with disseminated or chronic pulmonary histoplasmosis, and these levels should be documented in the medical record, as well as the physicians response to levels that are too low. 4. Itraconazole should not be given to patients receiving contraindicated medications (i.e., pimozide, quinidine, dofetilide, lovastatin, simvastatin, midazolam, and triazolam). Reasons for deviation from this practice should be documented in the medical record.
Acknowledgments
The expert panel wishes to express its gratitude to Drs. Larry Baddour, William E. Dismukes, and John R. Graybill for their thoughtful reviews of earlier drafts of the manuscript. The panel also wishes to thank Dr. Stanley C. Deresinski for his guidance throughout the guideline development process. Financial support. The Infectious Diseases Society of America. Potential conicts of interest. L.J.W. is President of MiraVista Diagnostics and MiraBella Technologies; he has research contracts with Astellas, Basilea, Schering-Plough, and Bio-Rad Laboratories and serves as a consultant to Bio-Rad Laboratories; L.J.W. is also a speaker for Bio-Rad and Enzon. J.W.B. has received research grants from Merck and Astellas and is on the speakers bureaus for Merck, Pzer, and Enzon. A.G.F. serves as a consultant for Enzon and as a speaker for Pzer, Merck, and Schering. C.A.K. has received research grants from Merck, Astellas, and ScheringPlough and is on the speakers bureaus for Merck, Pzer, Astellas, and Schering-Plough. D.S.M. is on the speakers bureaus of Merck and Pzer. M.B.K. and J.E.L.: no conicts.
APPENDIX A.
EXPERT PANEL Infectious diseases: L. Joseph Wheat (MiraVista Diagnostics, Indianapolis, IN), John W. Baddley (University of Alabama at Birmingham and Birmingham Veterans Affairs Medical Center), Alison G. Freifeld (University of Nebraska Medical Center, Omaha), Carol A. Kauffman (University of Michigan and Veterans Affairs Healthcare System, Ann Arbor), and David S. McKinsey (ID Associates of Kansas City, Kansas City, MO). Pediatric infectious diseases: Martin B. Kleiman (Indiana University School of Medicine, Indianapolis). Pulmonology: James E. Loyd (Vanderbilt University Medical Center, Nashville, TN)
References
1. Wheat J, Sarosi G, McKinsey D, et al. Practice guidelines for the management of patients with histoplasmosis. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:68895.
2. Field MJ, Lohr KN, eds; Institute of Medicine Committee to Advise the Public Health Service on Clinical Practice Guidelines. Clinical practice guidelines: directions for a new program. Washington, DC: National Academy Press, 1990:5577. 3. Canadian Task Force on the Periodic Health Examination. The periodic health examination. CMAJ 1979; 121:1193254. 4. Wheat LJ, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Semin Respir Crit Care Med 2004; 25:12944. 5. Oliver A, Ciulla TA, Comer GM. New and classic insights into presumed ocular histoplasmosis syndrome and its treatment. Curr Opin Ophthalmol 2005; 16:1605. 6. Giles CL, Falls HF. Amphotericin B therapy in the treatment of presumed histoplasma chorioretinitis: a further appraisal. Am J Ophthalmol 1968; 66:1014. 7. Sarosi GA, Voth DW, Dahl BA, Doto IL, Tosh FE. Disseminated histoplasmosis: results of long-term follow-up: a Center for Disease Control cooperative mycoses study. Ann Intern Med 1971; 75:5116. 8. Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efcacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002; 137:1059. 9. Perfect JR. Treatment of non-Aspergillus moulds in immunocompromised patients, with amphotericin B lipid complex. Clin Infect Dis 2005; 40(Suppl 6):S4018. 10. Dismukes WE, Bradsher RW Jr, Cloud GC, et al. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am J Med 1992; 93:48997. 11. Wheat J, Hafner R, Korzun AH, et al. Itraconazole treatment of disseminated histoplasmosis in patients with the acquired immunodeciency syndrome. AIDS Clinical Trial Group. Am J Med 1995; 98: 33642. 12. Kohler S, Wheat LJ, Connolly P, et al. Comparison of the echinocandin caspofungin with amphotericin B for treatment of histoplasmosis following pulmonary challenge in a murine model. Antimicrob Agents Chemother 2000; 44:18504. 13. Graybill JR, Najvar LK, Montalbo EM, Barchiesi FJ, Luther MF, Rinaldi MG. Treatment of histoplasmosis with MK-991 (L-743,872). Antimicrob Agents Chemother 1998; 42:1513. 14. Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic lamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998; 36:29506. 15. McKinsey DS, Kauffman CA, Pappas PG, et al. Fluconazole therapy for histoplasmosis. The National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1996; 23:9961001. 16. Wheat J, MaWhinney S, Hafner R, et al. Treatment of histoplasmosis with uconazole in patients with acquired immunodeciency syndrome. National Institute of Allergy and Infectious Diseases Acquired Immunodeciency Syndrome Clinical Trials Group and Mycoses Study Group. Am J Med 1997; 103:22332. 17. Wheat LJ, Connolly P, Smedema M, Brizendine E, Hafner R. Emergence of resistance to uconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeciency disease syndrome. Clin Infect Dis 2001; 33:19103. 18. Wheat LJ, Connolly P, Smedema M, et al. Activity of newer triazoles against Histoplasma capsulatum from patients with AIDS who failed uconazole. J Antimicrob Chemother 2006; 57:12359. 19. Connolly P, Wheat LJ, Schnizlein-Bick C, et al. Comparison of a new triazole, posaconazole, with itraconazole and amphotericin B for treatment of histoplasmosis following pulmonary challenge in immunocompromised mice. Antimicrob Agents Chemother 2000; 44:26048. 20. Al-Agha OM, Mooty M, Salarieh A. A 43-year-old woman with acquired immunodeciency syndrome and fever of undetermined origin: disseminated histoplasmosis. Arch Pathol Lab Med 2006; 130: 1203. 21. Hott JS, Horn E, Sonntag VK, Coons SW, Shetter A. Intramedullary
22.
23.
24. 25. 26.
27.
28. 29.
30.
31. 32.
33.
34.
35. 36. 37.
38.
39.
40.
41.
42.
histoplasmosis spinal cord abscess in a nonendemic region: case report and review of the literature. J Spinal Disord Tech 2003; 16:2125. Freifeld AG, Iwen PC, Lesiak BL, Gilroy RK, Stevens RB, Kalil AC. Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center. Transpl Infect Dis 2005; 7: 10915. Nath DS, Kandaswamy R, Gruessner R, Sutherland DE, Dunn DL, Humar A. Fungal infections in transplant recipients receiving alemtuzumab. Transplant Proc 2005; 37:9346. Truong MT, Sabloff BS, Munden RF, Erasmus JJ. A patient with newonset seizure and mediastinal adenopathy. Chest 2004; 126:9825. Restrepo A, Tobon A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007; 54:31927. Clark B, Foster R, Tunbridge A, Green S. A case of disseminated histoplasmosis successfully treated with the investigational drug posaconazole. J Infect 2005; 51:e17780. Pitisuttithum P, Negroni R, Graybill JR, et al. Activity of posaconazole in the treatment of central nervous system fungal infections. J Antimicrob Chemother 2005; 56:74555. Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet 1998; 35:46173. Hecht FM, Wheat J, Korzun AH, et al. Itraconazole maintenance treatment for histoplasmosis in AIDS: a prospective, multicenter trial. J Acquir Immune Dec Syndr Hum Retrovirol 1997; 16:1007. Glasmacher A, Hahn C, Molitor E, Marklein G, Sauerbruch T, Schmidt-Wolf IG. Itraconazole through concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropylbeta-cyclodextrin oral solution or coated-pellet capsules. Mycoses 1999; 42:591600. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50:15702. Purkins L, Wood N, Greenhalgh K, Allen MJ, Oliver SD. Voriconazole, a novel wide-spectrum triazole: oral pharmacokinetics and safety. Br J Clin Pharmacol 2003; 56(Suppl 1):106. Ullmann AJ, Cornely OA, Burchardt A, et al. Pharmacokinetics, safety, and efcacy of posaconazole in patients with persistent febrile neutropenia or refractory invasive fungal infection. Antimicrob Agents Chemother 2006; 50:65866. Gubbins PO, Krishna G, Sansone-Parsons A, et al. Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients. Antimicrob Agents Chemother 2006; 50:19939. Leveque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics of voriconazole. Int J Antimicrob Agents 2006; 27:27484. Wheat LJ. Improvements in diagnosis of histoplasmosis. Exp Opin Biol Ther 2006; 6:120721. Wheat LJ, Connolly P, Durkin M, Book BK, Pescovitz MD. Elimination of false-positive Histoplasma antigenemia caused by human anti-rabbit antibodies in the second-generation Histoplasma antigen assay. Transpl Infect Dis 2006; 8:21921. Wheat LJ, Witt J 3rd, Durkin M, Connolly P. Reduction in false antigenemia in the second generation Histoplasma antigen assay. Med Mycol 2007; 45:16971. Kuberski T, Myers R, Wheat LJ, et al. Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen. Clin Infect Dis 2007; 44:e504. Wheat LJ, Connolly P, Haddad N, Le Monte A, Brizendine E, Hafner R. Antigen clearance during treatment of disseminated histoplasmosis with itraconazole versus uconazole in patients with AIDS. Antimicrob Agents Chemother 2002; 46:24850. Wheat LJ, Connolly-Stringeld P, Blair R, Connolly K, Garringer T, Katz BP. Histoplasmosis relapse in patients with AIDS: detection using Histoplasma capsulatum variety capsulatum antigen levels. Ann Intern Med 1991; 115:93641. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004; 38:14859.
43. Haynes RR, Connolly PA, Durkin MM, et al. Antifungal therapy for central nervous system histoplasmosis, using a newly developed intracranial model of infection. J Infect Dis 2002; 185:18302. 44. LeMonte AM, Washum KE, Smedema ML, Schnizlein-Bick C, Kohler SM, Wheat LJ. Amphotericin B combined with itraconazole or uconazole for treatment of histoplasmosis. J Infect Dis 2000; 182: 54550. 45. Deepe GS Jr, Gibbons R. Recombinant murine granulocyte-macrophage colony-stimulating factor modulates the course of pulmonary histoplasmosis in immunocompetent and immunodecient mice. Antimicrob Agents Chemother 2000; 44:332836. 46. Clemons KV, Lutz JE, Stevens DA. Efcacy of interferon-gamma and amphotericin B for the treatment of systemic murine histoplasmosis. Microbes Infect 2001; 3:310. 47. Nosanchuk JD, Steenbergen JN, Shi L, Deepe GS Jr, Casadevall A. Antibodies to a cell surface histone-like protein protect against Histoplasma capsulatum. J Clin Invest 2003; 112:116475. 48. Zerbe CS, Holland SM. Disseminated histoplasmosis in persons with interferon-gamma receptor 1 deciency. Clin Infect Dis 2005; 41: e3841. 49. Kataria YP, Campbell PB, Burlingham BT. Acute pulmonary histoplasmosis presenting as adult respiratory distress syndrome: effect of therapy on clinical and laboratory features. South Med J 1981; 74: 5347, 42. 50. Brodsky AL, Gregg MB, Loewenstein MS, Kaufman L, Mallison GF. Outbreak of histoplasmosis associated with the 1970 Earth Day activities. Am J Med 1973; 54:33342. 51. Chamany S, Mirza SA, Fleming JW, et al. A large histoplasmosis outbreak among high school students in Indiana, 2001. Pediatr Infect Dis J 2004; 23:90914. 52. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine (Baltimore) 1981; 60:23166. 53. Parker JD, Sarosi GA, Doto IL, Bailey RE, Tosh FE. Treatment of chronic pulmonary histoplasmosis. N Engl J Med 1970; 283:2259. 54. Furcolow ML. Comparison of treated and untreated severe histoplasmosis. JAMA 1963; 183:1217. 55. Putnam LR, Sutliff WD, Larkin JC, et al. Histoplasmosis cooperative study: chronic pulmonary histoplasmosis treated with amphotericin B alone and with amphotericin B and triple sulfonamide. Am Rev Respir Dis 1968; 97:96102. 56. Sutliff WD, Andrews CE, Jones E, Terry RT. Histoplasmosis cooperative study: Veterans AdministrationArmed Forces Cooperative Study on histoplasmosis. Am Rev Respir Dis 1964; 89:64150. 57. Baum GL, Larkin JC Jr, Sutliff WD. Follow-up of patients with chronic pulmonary histoplasmosis treated with amphotericin B. Chest 1970; 58:5625. 58. Picardi JL, Kauffman CA, Schwarz J, Holmes JC, Phair JP, Fowler NO. Pericarditis caused by Histoplasma capsulatum. Am J Cardiol 1976; 37:828. 59. Wheat LJ, Stein L, Corya BC, et al. Pericarditis as a manifestation of histoplasmosis during two large urban outbreaks. Medicine (Baltimore) 1983; 62:1109. 60. Medeiros AA, Marty SD, Tosh FE, Chin TD. Erythema nodosum and erythema multiforme as clinical manifestations of histoplasmosis in a community outbreak. N Engl J Med 1966; 274:41520. 61. Rosenthal J, Brandt KD, Wheat LJ, Slama TG. Rheumatologic manifestations of histoplasmosis in the recent Indianapolis epidemic. Arthritis Rheum 1983; 26:106570. 62. Greenwood MF, Holland P. Tracheal obstruction secondary to Histoplasma mediastinal granuloma. Chest 1972; 62:6425. 63. Parish JM, Rosenow EC 3rd. Mediastinal granuloma and mediastinal brosis. Semin Respir Crit Care Med 2002; 23:13543. 64. Scully RE. Weekly clinicopathological exercises. Case 151991. A 48year-old man with dysphagia, chest pain, fever, and a subcarinal mass: case records of the Massachusetts General Hospital. N Engl J Med 1991; 324:104956. 65. Goodwin RA, Nickell JA, Des Prez RM. Mediastinal brosis compli-
66. 67.
68. 69.
70.
71. 72. 73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
cating healed primary histoplasmosis and tuberculosis. Medicine (Baltimore) 1972; 51:22746. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal brosis complicating histoplasmosis. Medicine (Baltimore) 1988; 67:295310. Peebles RS, Carpenter CT, Dupont WD, Loyd JE. Mediastinal brosis is associated with human leukocyte antigen-A2. Chest 2000; 117: 4825. Davis AM, Pierson RN, Loyd JE. Mediastinal brosis. Semin Respir Infect 2001; 16:11930. Martin JB, Prudhomme JB, Scott TA, Loyd JE. Features associated with mortality in brosing mediastinitis [abstract A57]. In: Proceedings of the American Thoracic Society (San Diego). 2005:A204. Urschel HC Jr, Razzuk MA, Netto GJ, Disiere J, Chung SY. Sclerosing mediastinitis: improved management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 1990; 50:21521. Dines DE, Payne WS, Bernatz PE, Pairolero PC. Mediastinal granuloma and brosing mediastinitis. Chest 1979; 75:3204. Mathisen DJ, Grillo HC. Clinical manifestation of mediastinal brosis and histoplasmosis. Ann Thorac Surg 1992; 54:10537; discussion 78. Doyle TP, Loyd JE, Robbins IM. Percutaneous pulmonary artery and vein stenting: a novel treatment for mediastinal brosis. Am J Respir Crit Care Med 2001; 164:65760. Goodwin RA Jr, Snell JD Jr. The enlarging histoplasmoma: concept of a tumor-like phenomenon encompassing the tuberculoma and coccidioidoma. Am Rev Respir Dis 1969; 100:112. Tobon AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmosis: a comparative study between patients with acquired immunodeciency syndrome and non-human immunodeciency virus-infected individuals. Am J Trop Med Hyg 2005; 73:57682. Nacher M, Sarazin F, El Guedj M, et al. Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation. J Acquir Immune Dec Syndr 2006; 41:46870. Shelburne SA 3rd, Visnegarwala F, Adams C, Krause KL, Hamill RJ, White AC Jr. Unusual manifestations of disseminated histoplasmosis in patients responding to antiretroviral therapy. Am J Med 2005; 118: 103841. McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeciency virus infection: randomized, placebo-controlled, double-blind study. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1999; 28:104956. Vail GM, Young RS, Wheat LJ, Filo RS, Cornetta K, Goldman M. Incidence of histoplasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area. Transpl Infect Dis 2002; 4:14851. Wallis RS, Broder M, Wong J, Lee A, Hoq L. Reactivation of latent granulomatous infections by iniximab. Clin Infect Dis 2005; 41(Suppl 3):S1948. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system: a clinical review. Medicine (Baltimore) 1990; 69:24460. Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005; 40: 84452. Schestatsky P, Chedid MF, Amaral OB, Unis G, Oliveira FM, Severo LC. Isolated central nervous system histoplasmosis in immunocompetent hosts: a series of 11 cases. Scand J Infect Dis 2006; 38:438. Groll AH, Giri N, Petraitis V, et al. Comparative efcacy and distri-
85.
86.
87. 88.
89.
90.
91. 92.
93. 94.
95.
96.
97.
98.
99. 100. 101. 102.
103. 104.
105.
bution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis 2000; 182:27482. Rivierez M, Heyman D, Brebion A, Landau-Ossondo M, Desbois N, Vally P. Spinal cord histoplasmoma: a case report. Neurochirurgie 2002; 48:448. Saccente M, McDonnell RW, Baddour LM, Mathis MJ, Bradsher RW. Cerebral histoplasmosis in the azole era: report of four cases and review. South Med J 2003; 96:4106. Paphitou NI, Barnett BJ. Solitary parietal lobe histoplasmoma mimicking a brain tumor. Scand J Infect Dis 2002; 34:22932. Basgoz N, Mattia AR. Case 41994a 38-year-old man with AIDS and the recent onset of diarrhea, hematochezia, fever, and pulmonary inltrates. N Engl J Med 1994; 330:27380. Rivera IV, Curless RG, Indacochea FJ, Scott GB. Chronic progressive CNS histoplasmosis presenting in childhood: response to uconazole therapy. Pediatr Neurol 1992; 8:1513. Goodpasture HC, Hershberger RE, Barnett AM, Peterie JD. Treatment of central nervous system fungal infection with ketoconazole. Arch Intern Med 1985; 145:87980. Bamberger DM. Successful treatment of multiple cerebral histoplasmomas with itraconazole. Clin Infect Dis 1999; 28:9156. Knapp S, Turnherr M, Dekan G, Willinger B, Stingl G, Rieger A. A case of HIV-associated cerebral histoplasmosis successfully treated with uconazole. Eur J Clin Microbiol Infect Dis 1999; 18:65861. Moudgal VV, Sobel JD. Antifungal drugs in pregnancy: a review. Exp Opin Drug Saf 2003; 2:47583. Whitt SP, Koch GA, Fender B, Ratnasamy N, Everett ED. Histoplasmosis in pregnancy: case series and report of transplacental transmission. Arch Intern Med 2004; 164:4548. Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996; 22:33640. Sorensen HT, Nielsen GL, Olesen C, et al. Risk of malformations and other outcomes in children exposed to uconazole in utero. Br J Clin Pharmacol 1999; 48:2348. Bar-Oz B, Moretti ME, Bishai R, et al. Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol 2000; 183:61720. Mastroiacovo P, Mazzone T, Botto LD, et al. Prospective assessment of pregnancy outcomes after rst-trimester exposure to uconazole. Am J Obstet Gynecol 1996; 175:164550. Odio CM, Navarrete M, Carrillo JM, Mora L, Carranza A. Disseminated histoplasmosis in infants. Pediatr Infect Dis J 1999; 18:10658. Leggiadro RJ, Barrett FF, Hughes WT. Disseminated histoplasmosis of infancy. Pediatr Infect Dis J 1988; 7:799805. Adderson EE. Histoplasmosis in a pediatric oncology center. J Pediatr 2004; 144:1006. Fojtasek MF, Kleiman MB, Connolly-Stringeld P, Blair R, Wheat LJ. The Histoplasma capsulatum antigen assay in disseminated histoplasmosis in children. Pediatr Infect Dis J 1994; 13:8015. Little JA. Histoplasmosis in childhood. Q Rev Pediatr 1962; 17:326. Tobon AM, Franco L, Espinal D, et al. Disseminated histoplasmosis in children: the role of itraconazole therapy. Pediatr Infect Dis J 1996; 15:10028. Clapp DW, Kleiman MB, Brahmi Z. Immunoregulatory lymphocyte populations in disseminated histoplasmosis of infancy. J Infect Dis 1987; 156:6878.

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IDSA Guidelines for Management of Histoplasmosis CID 2007:45 (1 October) 807

Treatment of Acute and Chronic Pulmonary Histoplasmosis

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Recommendations for the treatment of histoplasmosis.

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